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PIK3CA alterations in Middle Eastern ovarian cancers.

Abubaker J, Bavi P, Al-Haqawi W, Jehan Z, Munkarah A, Uddin S, Al-Kuraya KS - Mol. Cancer (2009)

Bottom Line: PIK3CA amplification was seen in 54 of 152 (35.5%) EOC cases analyzed; PIK3CA gene mutations in 6/153 EOC (3.9%); KRAS mutations in 3/154 EOC (1.9%), BRAF mutations in 3/156 EOC (1.9%), p53 mutation in 50/154 EOC (32.5%), and loss of PTEN protein expression in 33/144 EOC (22.9%). p110 alpha overexpression was associated with increased phosphorylation of AKT-Ser 473 and with the proliferation marker Ki-67.Our data showed mutual exclusivity between the molecular event of PIK3CA amplification and mutations in PIK3CA, KRAS, BRAF genes, which suggests that each of these alterations may individually be sufficient to drive ovarian tumor pathogenesis independently.High prevalence of genetic alterations in PI3K/AKT pathway in a Middle Eastern ovarian carcinoma provides genetic evidence supporting the notion that dysregulated PI3K/AKT pathways play an important role in the pathogenesis of ovarian cancers.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. jabubakr@kfshrc.edu.sa

ABSTRACT

Background: PI3K/AKTsignaling pathway plays an important role in cell growth, proliferation, and tumorgenesis of various malignancies. This signaling pathway has been shown to be frequently altered in several human cancers including ovarian cancers. However the role of this oncogenic signaling pathway has not been explored in the Middle Eastern epithelial ovarian cancer (EOC). Therefore, we investigated PI3K/AKT genetic alterations such as PIK3CA amplification, PIK3CA mutation, PTEN protein loss and their relationships with various clinicopathological characteristics in 156 EOCs.

Results: Fluorescence in situ hybridization (FISH) technique and DNA sequencing were used to analyze PIK3CA amplification and mutation respectively. Expression of PIK3CA protein expression (p110 alpha), PTEN, p-AKT and Ki-67 was analyzed by immunohistochemistry. PIK3CA amplification was seen in 54 of 152 (35.5%) EOC cases analyzed; PIK3CA gene mutations in 6/153 EOC (3.9%); KRAS mutations in 3/154 EOC (1.9%), BRAF mutations in 3/156 EOC (1.9%), p53 mutation in 50/154 EOC (32.5%), and loss of PTEN protein expression in 33/144 EOC (22.9%). p110 alpha overexpression was associated with increased phosphorylation of AKT-Ser 473 and with the proliferation marker Ki-67.

Conclusion: Our data showed mutual exclusivity between the molecular event of PIK3CA amplification and mutations in PIK3CA, KRAS, BRAF genes, which suggests that each of these alterations may individually be sufficient to drive ovarian tumor pathogenesis independently. High prevalence of genetic alterations in PI3K/AKT pathway in a Middle Eastern ovarian carcinoma provides genetic evidence supporting the notion that dysregulated PI3K/AKT pathways play an important role in the pathogenesis of ovarian cancers.

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Immunohistochemical analysis of p-AKT, PI3K-110 alpha subunit protein expression and PTEN in epithelial ovarian carcinoma (EOC). (i) p-AKT over expression was observed along with (iii) low PTEN expressionand (v) over expression of PI3K-110 alpha in EOC TMA specimen and, (ii) Low expression for p-AKT was seen along with (iv) high PTEN expression and (vi) reduced expression for PI3K-110 alpha in EOC TMA specimen. 20 × magnifications with the inset showing a 100 × magnified view of the same.
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Figure 3: Immunohistochemical analysis of p-AKT, PI3K-110 alpha subunit protein expression and PTEN in epithelial ovarian carcinoma (EOC). (i) p-AKT over expression was observed along with (iii) low PTEN expressionand (v) over expression of PI3K-110 alpha in EOC TMA specimen and, (ii) Low expression for p-AKT was seen along with (iv) high PTEN expression and (vi) reduced expression for PI3K-110 alpha in EOC TMA specimen. 20 × magnifications with the inset showing a 100 × magnified view of the same.

Mentions: PIK3CA mutation was seen in 6 of 153 (3.9%, Fig. 1) EOC's analyzed and FISH analysis revealed the presence of PIK3CA amplification in 54 of 152 (35.5%, Fig. 2) EOC cases analyzed. PIK3CA amplification results were further validated by real-time PCR. No significant associations were observed with PIK3CA mutations or PIK3CA amplifications and clinicopathological parameters. Immunohistochemical analysis showed overexpression of p110 α expression in 78 of 140 (55.7%, Fig. 3) EOC cases analyzed and its association with various clinicopathological parameters was analyzed (Table 2). p110 α expression overexpression did not coorelate with age, tumor stage, FIGO grade and progreesion free survival. PIK3CA 110 overexpression was associated with overexpression of p-AKT-Ser 473 (p = 0.0260) and a trend was noted with the proliferation marker Ki-67 (p = 0.0639). Of the 6 EOCS with PIK3CA mutation, 5 of them showed overexpression of PIK3CA 110 protein. No association was seen with PIK3CA amplification and overexpression of p110 α expression (p = 0.2320).


PIK3CA alterations in Middle Eastern ovarian cancers.

Abubaker J, Bavi P, Al-Haqawi W, Jehan Z, Munkarah A, Uddin S, Al-Kuraya KS - Mol. Cancer (2009)

Immunohistochemical analysis of p-AKT, PI3K-110 alpha subunit protein expression and PTEN in epithelial ovarian carcinoma (EOC). (i) p-AKT over expression was observed along with (iii) low PTEN expressionand (v) over expression of PI3K-110 alpha in EOC TMA specimen and, (ii) Low expression for p-AKT was seen along with (iv) high PTEN expression and (vi) reduced expression for PI3K-110 alpha in EOC TMA specimen. 20 × magnifications with the inset showing a 100 × magnified view of the same.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724395&req=5

Figure 3: Immunohistochemical analysis of p-AKT, PI3K-110 alpha subunit protein expression and PTEN in epithelial ovarian carcinoma (EOC). (i) p-AKT over expression was observed along with (iii) low PTEN expressionand (v) over expression of PI3K-110 alpha in EOC TMA specimen and, (ii) Low expression for p-AKT was seen along with (iv) high PTEN expression and (vi) reduced expression for PI3K-110 alpha in EOC TMA specimen. 20 × magnifications with the inset showing a 100 × magnified view of the same.
Mentions: PIK3CA mutation was seen in 6 of 153 (3.9%, Fig. 1) EOC's analyzed and FISH analysis revealed the presence of PIK3CA amplification in 54 of 152 (35.5%, Fig. 2) EOC cases analyzed. PIK3CA amplification results were further validated by real-time PCR. No significant associations were observed with PIK3CA mutations or PIK3CA amplifications and clinicopathological parameters. Immunohistochemical analysis showed overexpression of p110 α expression in 78 of 140 (55.7%, Fig. 3) EOC cases analyzed and its association with various clinicopathological parameters was analyzed (Table 2). p110 α expression overexpression did not coorelate with age, tumor stage, FIGO grade and progreesion free survival. PIK3CA 110 overexpression was associated with overexpression of p-AKT-Ser 473 (p = 0.0260) and a trend was noted with the proliferation marker Ki-67 (p = 0.0639). Of the 6 EOCS with PIK3CA mutation, 5 of them showed overexpression of PIK3CA 110 protein. No association was seen with PIK3CA amplification and overexpression of p110 α expression (p = 0.2320).

Bottom Line: PIK3CA amplification was seen in 54 of 152 (35.5%) EOC cases analyzed; PIK3CA gene mutations in 6/153 EOC (3.9%); KRAS mutations in 3/154 EOC (1.9%), BRAF mutations in 3/156 EOC (1.9%), p53 mutation in 50/154 EOC (32.5%), and loss of PTEN protein expression in 33/144 EOC (22.9%). p110 alpha overexpression was associated with increased phosphorylation of AKT-Ser 473 and with the proliferation marker Ki-67.Our data showed mutual exclusivity between the molecular event of PIK3CA amplification and mutations in PIK3CA, KRAS, BRAF genes, which suggests that each of these alterations may individually be sufficient to drive ovarian tumor pathogenesis independently.High prevalence of genetic alterations in PI3K/AKT pathway in a Middle Eastern ovarian carcinoma provides genetic evidence supporting the notion that dysregulated PI3K/AKT pathways play an important role in the pathogenesis of ovarian cancers.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. jabubakr@kfshrc.edu.sa

ABSTRACT

Background: PI3K/AKTsignaling pathway plays an important role in cell growth, proliferation, and tumorgenesis of various malignancies. This signaling pathway has been shown to be frequently altered in several human cancers including ovarian cancers. However the role of this oncogenic signaling pathway has not been explored in the Middle Eastern epithelial ovarian cancer (EOC). Therefore, we investigated PI3K/AKT genetic alterations such as PIK3CA amplification, PIK3CA mutation, PTEN protein loss and their relationships with various clinicopathological characteristics in 156 EOCs.

Results: Fluorescence in situ hybridization (FISH) technique and DNA sequencing were used to analyze PIK3CA amplification and mutation respectively. Expression of PIK3CA protein expression (p110 alpha), PTEN, p-AKT and Ki-67 was analyzed by immunohistochemistry. PIK3CA amplification was seen in 54 of 152 (35.5%) EOC cases analyzed; PIK3CA gene mutations in 6/153 EOC (3.9%); KRAS mutations in 3/154 EOC (1.9%), BRAF mutations in 3/156 EOC (1.9%), p53 mutation in 50/154 EOC (32.5%), and loss of PTEN protein expression in 33/144 EOC (22.9%). p110 alpha overexpression was associated with increased phosphorylation of AKT-Ser 473 and with the proliferation marker Ki-67.

Conclusion: Our data showed mutual exclusivity between the molecular event of PIK3CA amplification and mutations in PIK3CA, KRAS, BRAF genes, which suggests that each of these alterations may individually be sufficient to drive ovarian tumor pathogenesis independently. High prevalence of genetic alterations in PI3K/AKT pathway in a Middle Eastern ovarian carcinoma provides genetic evidence supporting the notion that dysregulated PI3K/AKT pathways play an important role in the pathogenesis of ovarian cancers.

Show MeSH
Related in: MedlinePlus